tbuckley/cabot-search huggingface dataset:
P1068: RISK-ADJUSTED SAFETY ANALYSIS OF PACRITINIB IN PATIENTS WITH MYELOFIBROSIS
Authors: A. Vannucchi, N. Pemmaraju, B. Scott, M. Savona, S. Oh, F. Palandri, H. K. Al-Ali, M. Sobas, M. F. McMullin, V. Gupta, A. Yacoub, R. Mesa, S. Buckley, K. Roman-Torres, S. Verstovsek, C. Harrison
Journal: HemaSphere (2022)

Background: Pacritinib is a novel JAK2/IRAK1 inhibitor that has shown clinically significant activity in patients with myelofibrosis, including those with platelet counts <50 x 109/L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. Aims: This safety analysis focuses on these toxicities of interest for patients treated with pacritinib 200 mg twice daily (BID) and best available therapy (BAT), including ruxolitinib, on the phase 3 PERSIST-2 and phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Patients treated with pacritinib 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT, including ruxolitinib on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years, were calculated for the following: overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (by SMQ), major cardiac events (determined by major adverse cardiovascular events [MACE] classification), infections, thromboses, and secondary malignancies. Results: A total of 160 patients were analyzed as the pooled pacritinib 200 mg BID group (n=106 in PERSIST-2; n=54 in PAC203) and 98 patients in the BAT group (44 on ruxolitinib). At baseline, the median platelet count was 57 x 109/L for the pooled pacritinib group and BAT group; hemoglobin was 9.2 vs 9.7 g/dL and 66% vs 53% had prior JAK2 inhibitor therapy respectively. The rate of AEs was higher on pacritinib versus BAT, while the rate of fatal AEs was lower (Table 1). Both bleeding and cardiac events occurred at slightly lower rates on pacritinib compared to BAT. There were no MACE for pacritinib, whereas there were for BAT, including in patients treated with ruxolitinib. Malignant neoplasms (excluding worsening myelofibrosis and leukemia) occurred at similar rates on pacritinib and BAT, though rate of non-melanoma skin cancers was lower in the pooled pacritinib group (3/100 patient-years) versus BAT (7/100 patient-years), including ruxolitinib (11/100 patient-years). Infection occurred more frequently on pacritinib versus BAT, though fungal and viral infections occurred less frequently, as did Herpes Zoster reactivation (pooled pacritinib: 0/100 patient-years vs BAT: 2.4/100 patient-years, including ruxolitinib: 5.5/100 patient-years). Thrombosis occurred at similar rates on pacritinib and BAT. Image:Summary/Conclusion: Risk-adjusted analysis demonstrates that the safety profile of pacritinib 200 mg BID is comparable or superior to BAT, including ruxolitinib. Pacritinib 200 mg BID may represent a full-dose therapeutic option for patients with myelofibrosis, including those with thrombocytopenia.
Evaluation of Acute Adverse Events after Covid-19 Vaccination during Pregnancy
Authors: Malini DeSilva, Jacob Haapala, Gabriela Vazquez-Benitez, Kimberly K Vesco, Matthew F Daley, Darios Getahun, Ousseny Zerbo, Allison Naleway, Jennifer C Nelson, Joshua T B Williams, Simon J Hambidge, Thomas G Boyce, Candace C Fuller, Heather S Lipkind, Eric Weintraub, Michael M McNeil, Elyse O Kharbanda
Journal: New England Journal of Medicine (2022)

Evaluation of Acute Adverse Events after Covid-19Vaccination during Pregnancy 1 to 7 days after vaccination Fever Malaise
Death of a Parent and the Risk of Ischemic Heart Disease and Stroke in Denmark and Sweden
Authors: Hua Chen, Jiong Li, Dang Wei, Mikael Rostila, Imre Janszky, Yvonne Forsell, Tomas Hemmingsson, Krisztina D. László
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Increasing evidence suggests that parental death is associated with unhealthy behaviors and mental ill-health. Knowledge regarding the link between parental death and the risk of ischemic heart disease (IHD) and stroke remains limited. <h3>Objectives</h3> To investigate whether parental death is associated with an increased risk of IHD and stroke and whether these associations differ by the characteristics of the loss. <h3>Design, Setting, and Participants</h3> This population-based cohort study, involving linkages between several nationwide registers, included 3 766 918 individuals born between 1973 and 1998 in Denmark and between 1973 and 1996 in Sweden. Participants were followed up until 2016 in Denmark and 2014 in Sweden. Data were analyzed from December 2019 to May 2021. <h3>Exposures</h3> Death of a parent. <h3>Main Outcomes and Measures</h3> Diagnosis with or death due to IHD or stroke. Poisson regression was used to analyze the associations between parental death and IHD and stroke risk. <h3>Results</h3> Altogether, 48.8% of the participants were women, and 42.7% were from Denmark. A total of 523 496 individuals lost a parent during the study period (median age at loss, 25 years; IQR, 17-32 years). Parental death was associated with a 41% increased risk of IHD (incidence rate ratio [IRR], 1.41; 95% CI, 1.33-1.51) and a 30% increased risk of stroke [IRR, 1.30; 95% CI, 1.21-1.38). The associations were observed not only if the parent died because of cardiovascular or other natural causes but also in cases of unnatural deaths. The associations were stronger when both parents had died (IHD: IRR, 1.87; 95% CI, 1.59-2.21; stroke: IRR, 1.64; 95% CI, 1.35-1.98) than when 1 parent had died (IHD: IRR, 1.37; 95% CI, 1.28-1.47; stroke: IRR, 1.27; 95% CI, 1.19-1.36) but did not differ substantially by the offspring's age at loss or the deceased parents' sex. The risk of acute myocardial infarction was highest in the first 3 months after loss. <h3>Conclusions and Relevance</h3> In this cohort study, parental death in the first decades of life was associated with an increased risk of IHD and stroke. The associations were observed not only in cases of parental cardiovascular and other natural deaths but also in cases of unnatural deaths. Family members and health professionals may need to pay attention to the cardiovascular disease risk among parentally bereaved individuals.
Bioengineering Human Tissues and the Future of Vascular Replacement
Authors: Kaleb M. Naegeli, Mehmet H. Kural, Yuling Li, Juan Wang, Emmanuelle A. Hugentobler, Laura E. Niklason
Journal: Circulation Research (2022)

Cardiovascular defects, injuries, and degenerative diseases often require surgical intervention and the use of implantable replacement material and conduits. Traditional vascular grafts made of synthetic polymers, animal and cadaveric tissues, or autologous vasculature have been utilized for almost a century with well-characterized outcomes, leaving areas of unmet need for the patients in terms of durability and long-term patency, susceptibility to infection, immunogenicity associated with the risk of rejection, and inflammation and mechanical failure. Research to address these limitations is exploring avenues as diverse as gene therapy, cell therapy, cell reprogramming, and bioengineering of human tissue and replacement organs. Tissue-engineered vascular conduits, either with viable autologous cells or decellularized, are the forefront of technology in cardiovascular reconstruction and offer many benefits over traditional graft materials, particularly in the potential for the implanted material to be adopted and remodeled into host tissue and thus offer safer, more durable performance. This review discusses the key advances and future directions in the field of surgical vascular repair, replacement, and reconstruction, with a focus on the challenges and expected benefits of bioengineering human tissues and blood vessels.
P599: RARE GERMLINE VARIANTS IN ATM INFLUENCE THE PATHOGENESIS OF CLL
Authors: B. L. Lampson, A. Gupta, S. Tyekucheva, Z. Wang, N. Wojciechowska, C. J. Shaughnessy, P. O. Baker, S. M. Fernandes, A. S. Kim, J. R. Brown
Journal: HemaSphere (2022)

Background: Germline missense variants of unknown significance (VUS) are increasingly identified in cancer-related genes by next generation sequencing. The ATM gene on chromosome 11 is a tumor suppressor gene that is frequently deleted or mutated in CLL, and also carries over 1,000 germline missense VUS. Aims: We sought to evaluate whether germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared to other hematologic malignancies and whether they influence the clinical characteristics of CLL. We sought to determine whether one of the most common VUS has an impact on ATM function. Methods: In our hematologic malignancy clinic, we identified 3,128 patients (including 825 CLL patients), who underwent clinical-grade sequencing of the entire coding region of ATM between 2014 and 2019. We evaluated the frequencies of germline ATM variants in different hematologic neoplasms. In patients with CLL, we determined whether these variants affect CLL-associated characteristics such as somatic 11q deletion. Finally we generated an ATML2307F knock-in cell line to characterize the functional impact of the L2307F VUS on response to etoposide treatment or irradiation. Results: Germline ATM variants are present in 24% of patients with CLL, significantly higher than in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). CLL patients with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of CLL patients and is associated with a three-fold increase in rates of somatic 11q-deletion. CLL in patients with two other common ATM VUS, p.S707P and p.F858L, was also significantly enriched for ATM-aberrant disease. Cell-based assays evaluating response to etoposide treatment or irradiation demonstrated that ATM p.L2307F shows hypomorphic function. Summary/Conclusion: Germline ATM variants cluster within CLL and affect the phenotype of the CLL that develops, implying that some of these variants (such as ATML2307F) have functional significance and should not be ignored. Further larger studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.
P1479: A BASELINE AUDIT OF THE USE A VALIDATED PSYCHOMETRIC TOOL (ASCQ-ME) TO ASSESS THE UNMET PSYCHOLOGICAL NEEDS OF A 2021 COHORT OF PATIENTS LIVING WITH SICKLE CELL
Authors: K. Kelleher, V. Garcia, R. Auturally, R. Jolley, R. Marks, M. Besser
Journal: HemaSphere (2022)

Background: Adults living with inherited red cell disorders face myriad social and emotional challenges. While the literature highlights higher incidence rates of depression and anxiety in those with sickle cell disease (SCD) compared to the general population, granular data on the specific emotional experience of these people is missing, resulting in boundaries to accessing mental health care. New disease modifying drugs can now preferentially increase haemoglobin with relatively small impact on crisis frequency or reduce crisis frequency with minimum impact on haemoglobin. Current management of patients still focuses on pain crisis and crisis prevention. At the time of this study, in the UK, hydroxycarbamide and exchange transfusion were the only available disease modifying therapies. Aims: This study aimed to quantify psycho-social functioning and more accurately identify multifactorial level of need in patients living with SCD. Methods: The present study used a validated, detailed, psychometric test, the Adult Sickle Cell Questionnaire Measure (ASCQ-Me), to identify need in a population of adults living with SCD in Cambridge. Self-report ASCQ-Me data was collected from patients (N=59) first on how SCD has affected 5 domains of psych-social impact (emotional, pain, sleep, social, stiffness), and second about the frequency and severity of sickle crisis. Demographic data was recorded based on sickle genotype, age, sex, disease modification, whether patients had fatigue, and whether patients requested counselling at the time of annual review. Results: Patients who reported fatigue had significantly lower scores across all 5 domains of psychological impact than patients that did not report fatigue. However, there was no difference in Hb or HbF levels. When patients were split by disease modification (hydroxycarbamide, exchange transfusion, or no modification) there seemed to be a trend towards worsening psychological impact in all 5 domains for patients in the exchange group, with better outcomes from patients on hydroxycarbamide. There was no significant difference in psychological impact scores when patients were split by sex or sickle genotype. In particular, there was a trend towards higher frequency, but reduced intensity of pain crisis in patients with SC disease, but this did not reach significance. Patients who stated that they would like to be referred for psychological counselling also showed significantly worse scores across all 5 domains of psychological impact. Image:Summary/Conclusion: There is an unmet need in providing psychological support for patients with complex diseases like sickle cell. Our finding that the subjective feeling of fatigue is associated with a multidimensional lower performance in the ASCQ-Me, in addition to disease modifying therapy, psychological support will remain very important and should not be attributed to anaemia alone.
P1475: THE ROLE OF BCL11A AND HBS1L-MYB SINGLE NUCLEOTIDE POLYMORPHISMS IN EGYPTIAN SICKLE CELL DISEASE PATIENTS
Authors: A. El Maraashly
Journal: HemaSphere (2022)

Background: Sickle cell disease (SCD) is a debilitating blood disorder with a highly variable phenotype. Inter-individual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. The only currently FDA-approved HbF inducing drug for sickle cell disease (SCD) is hydroxyurea (HU). Genome wide association studies (GWAS) have identified three major quantitative trait loci (QTL) (intergenic region of HBS1L-MYB, BCL11A gene and XmnI site) associated with HbF. Several single nucleotide polymorphisms (SNPs) with persistence of HbF and amelioration of disease severity of β-thalassemia (β-thal) and SCD have been identified. Aims: The aim of the current study is to find the influence of these genetic modifiers, especially BCL11A (rs4671393) and HBS1L-MYB intergenic region (rs9399137) SNPs on the level of HbF, severity of SCD and response to hydroxyurea in Egyptian sickle cell disease patients. Methods: The present study included 100 patients with SCD; 56 patients were diagnosed as homozygous sickle cell anemia (SS) patients, while 44 patients were diagnosed as sickle beta thalassemia patients (Sβ). Genotyping for the genes was done by Real-Time PCR (RT-PCR) technique. Results: BCL11A (rs4671393) SNP showed higher hemoglobin and HbF levels when induced with HU, with significantly higher increment in HbF level post HU therapy as well as a milder clinical phenotype in our Sβ patients’ group. In our SS patients’ group it showed a lower incidence of pneumonia as well as a more effective response to HU treatment. HBS1L-MYB intergenic region (rs9399137) SNPs showed lower reticulocytic counts and serum ferritin levels in our Sβ patients’ group. Summary/Conclusion: In conclusion, our study shows that BCL11A (rs4671393) SNP showed higher hemoglobin and HbF levels when induced with HU, with significantly higher increment in HbF level post HU therapy as well as a milder clinical phenotype in our Egyptian study.
Effectiveness and Safety of Early Initiation of Poststernotomy Cardiac Rehabilitation Exercise Training
Authors: Stuart Ennis, Grace Lobley, Sandra Worrall, Becky Evans, Peter K. Kimani, Amir Khan, Richard Powell, Prithwish Banerjee, Tom Barker, Gordon McGregor
Journal: JAMA Cardiology (2022)

Guidelines recommend that cardiac rehabilitation (CR) exercise training should not start until 6 weeks after sternotomy, although this is not evidence based. Limited data suggest that starting earlier is not detrimental, but clinical trials are needed.To compare the effectiveness and safety of CR exercise training started either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy.This was an assessor-blind, noninferiority, parallel-group, randomized clinical trial that conducted participant recruitment from June 12, 2017, to March 17, 2020. Participants were consecutive cardiac surgery sternotomy patients recruited from 2 outpatient National Health Service rehabilitation centers: University Hospital, Coventry, UK, and Hospital of St Cross, Rugby, UK.Participants were randomly assigned to 8 weeks of twice-weekly supervised CR exercise training starting either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy. Exercise training adhered to existing guidelines, including functional strength and cardiovascular components.Outcomes were assessed at baseline (inpatient after surgery), after CR (10 or 14 weeks after sternotomy), and 12 months after randomization. The primary outcome was the change in 6-minute walk test distance from baseline to after CR. Secondary outcomes included safety, functional fitness, and quality of life.A total of 158 participants (mean [SD] age, 63 [11.5] years, 133 male patients [84.2%]) were randomly assigned to study groups; 118 patients (usual-care CR, 61 [51.7%]; early CR, 57 [48.3%]) were included in the primary analysis. Early CR was not inferior to usual-care CR (noninferiority margin, 35 m); the mean change in 6-minute walk distance from baseline to after CR was 28 m greater in the early CR group (95% CI, -11 to 66; P = .16). Mean differences for secondary outcomes were not statistically significant, indicating noninferiority of early CR. There were 46 vs 58 adverse events and 14 vs 18 serious adverse events in usual-care CR and early CR, respectively. There was no difference between the groups in the likelihood of participants having an adverse or serious adverse event.Starting exercise training from 2 weeks after sternotomy was as effective as starting 6 weeks after sternotomy for improving 6-minute walk distance. With appropriate precautions, clinicians and CR professionals can consider starting exercise training as early as 2 weeks after sternotomy.ClinicalTrials.gov Identifier: NCT03223558.
P1457: DEMOGRAPHICS AND TREATMENT OUTCOMES IN PATIENTS WITH EBV+ PTLD TREATED WITH OFF-THE-SHELF EBV-SPECIFIC CTL (TABELECLEUCEL) UNDER AN ONGOING EXPANDED ACCESS PROGRAM IN EUROPE: FIRST ANALYSES
Authors: S. Choquet, B. Uttenthal, S. Chaganti, P. Comoli, R. Trappe, A. Friedetzky, B. Xing, X. Li, T. Polak, L. Gamelin, J.-H. Terwey, D. Dierickx
Journal: HemaSphere (2022)

Background: Patients undergoing allogeneic hematopoietic cell transplant (HCT) or solid organ transplant (SOT) are at risk of developing Epstein–Barr virus driven post-transplant lymphoproliferative disorder (EBV+ PTLD), a rare hematologic malignancy, which is often aggressive and life-threatening. Patients with relapsed or refractory (r/r) EBV+ PTLD have few treatment options with poor outcomes, demonstrating a clear unmet medical need. Tabelecleucel is an investigational, off-the-shelf, allogeneic EBV-specific T-cell immunotherapy being studied in patients with serious EBV+ diseases (NCT04554914 & NCT03394365) that has demonstrated clinical benefit and favorable safety profile in the treatment of EBV+ PTLD after failure of rituximab (R) ± chemotherapy (Prockop, EBMT 2021, ATC 2021, ASH 2021). Aims: First analyses of demographics, efficacy and safety results of r/r EBV+ PTLD patients following SOT or HCT who presented between Jul 2020 and Nov 2021 and consented to research. Methods: Atara Biotherapeutics supports an ongoing expanded access program (EAP) in Europe for patients with EBV+ diseases who have no other treatment options. Demographics, efficacy and safety data of r/r EBV+ PTLD patients following SOT or HCT who presented to the EAP between Jul 2020 and Nov 2021 and consented to research were analyzed. Results: A total of 48 EAP requests from 9 countries for patients with EBV+ diseases were received. Twenty-two patients from 7 countries consented to this research: 16 EBV+ PTLD and 6 EBV+ non-PTLD. Of the 16 PTLD patients 15 received at least one dose of tabelecleucel. Overall, 9 out of 15 (60%) patients achieved a response as assessed by the treating physician, with 6 complete responses and 3 partial responses. Eight out of nine responses were seen after the first cycle. No adverse events were reported as related to tabelecleucel by the treating physician. Image:Summary/Conclusion: The successful execution of this European EAP demonstrates the feasibility to deliver an off-the-shelf allogeneic EBV+ T-cell therapy in time-sensitive clinical situations when no other treatment options exist. These data show clinically meaningful outcomes for patients with r/r EBV+PTLD post-SOT or post-HCT treated with tabelecleucel consistent with previously reported favorable safety and efficacy profile (Prockop, ASH 2021).
S232: EXPANDING THE REPERTOIRE OF HLA CLASS I-RESTRICTED MINOR HISTOCOMPATIBILITY ANTIGENS FOR IMMUNE MONITORING AND MODULATION AFTER ALLOGENEIC STEM CELL TRANSPLANTATION
Authors: K. Fuchs, M. van de Meent, W. Honders, C. van Bergen, J. F. Falkenburg, M. Griffioen
Journal: HemaSphere (2022)

Background: Allogeneic stem cell transplantation is given as curative treatment for hematological malignancies, but patients face the risk of relapse of their malignancy as well as Graft-versus-Host Disease. After transplantation, donor T cells recognize polymorphic peptides presented by HLA surface molecules on the patient’s cells. These polymorphic peptides, called minor histocompatibility antigens, are caused by genetic differences in single nucleotide polymorphisms (SNPs) between patient and donor. Dependent on whether the antigen is presented on tumor cells or healthy non-hematopoietic tissues of the patient, donor T cells may induce the favourable Graft-versus-Leukemia effect or Graft-versus-Host-Disease, respectively. Aims: The aim is to identify the dominant repertoire of minor histocompatibility antigens in seven common HLA class I molecules for immune monitoring and modulation after allogeneic stem cell transplantation. Methods: Donor T cells isolated from patients after allogeneic stem cell transplantation are tested for recognition of a new panel of 191 selected B cell lines, which are sequenced in the 1000 Genomes Project. This panel enables the inclusion of seven common HLA class I molecules and increases SNP coverage to 11 million (MAF > 0.01). SNPs that strongly associate with T cell recognition are subsequently validated to encode minor histocompatibility antigens. Results: Using an optimized approach for whole genome association scanning, more than 80 new minor histocompatibility antigens have been found that are presented by seven common HLA class I molecules. Antigens targeted in immune responses after transplantation were often shared between patients, and about 25-30% of antigens were translated in other reading frames than human proteins with known function. Furthermore, the extended repertoire was investigated for T cell frequency and tissue distribution of antigen-encoding genes, pointing towards several antigens as potential targets for immunotherapy. Summary/Conclusion: In conclusion, despite many SNP mismatches between patients and donors, our data demonstrate that the repertoire of minor histocompatibility antigens is confined. As the antigens were identified by an unbiased forward strategy (T cell-to-antigen), our collection provides relevant insight into the various sources of antigens in annotated and unannotated reading frames, which is essential for accurate antigen prediction by reverse strategies (antigen-to-T cell). Furthermore, we more than doubled the number of minor histocompatibility antigens which are fundamental to predict, follow or manipulate immune responses after allogeneic stem cell transplantation to improve clinical outcome of transplanted patients.